S128: AML CONDITIONING OF THE BONE MARROW MICROENVIRONMENT THROUGH CCR1 LIGAND UP-REGULATION PROMOTES AML STEM CELL PROPAGATION AND IS MIMICKED BY AGEING
Authors: Xiying Ren, Alexander Thomas, Yiran Meng, Claus Nerlov, Simona Valletta
Journal: HemaSphere (2023)

Background: The prevalence of acute myeloid leukaemia (AML) increases dramatically with age. Although some evidence suggests that age-related bone marrow (BM) microenvironmental changes might contribute to the development of myeloid malignancies, whether and how the aged BM microenvironment facilitates AML progression remains unknown. In addition, most elderly patients are not eligible for intensive chemotherapy and have poor prognoses; therefore, novel therapeutic strategies are needed. Aims: Firstly, to explore the possibility that ageing and AML exposure have similar effects on the BM microenvironment and that the overlapping features of the two conditions play a role in leukaemia initiating/stem cell (LIC/LSC) propagation. Secondly, to identify the cell surface receptor gene/signalling pathway that could potentially be used as novel therapeutic targets in elderly AML. Methods:A Cebpa mutant AML (CM-AML) mouse model dependent on the BM microenvironment was used. Systematic transcriptional profiling of the LICs and leukaemic BM stromal cells was performed using bulk RNA sequencing (RNAseq), and the transcriptional changes were correlated with those occurring during ageing. Functional interrogation of the candidate cell surface receptor gene was performed using CRISPR-Cas9 for in vivo gene knockout. A selective inhibitor of the identified candidate receptor was used for in vivo validation experiments. Results: We identified specific and significant conservation of process networks de-regulated in the LICs and in both aged and AML-exposed vascular endothelial cells (VECs) during leukaemia expansion (Figure 1A). Furthermore, when the CM-AML LICs were transplanted into non-conditioned mice, little or no leukaemia engraftment was observed in the unperturbed young BM. In contrast, the LICs engrafted and propagated with high efficiency in the aged BM (Figure 1B). These findings demonstrate that the aged and leukaemic BM microenvironments are transcriptionally and functionally alike and suggest that the aged BM microenvironment can support AML expansion more effectively than that of the young mice. Then, we reasoned that specific cytokine/chemokine signalling could facilitate age-related AML propagation. We focused on CCR1 signalling as Ccr1 overexpression alongside CCR1 ligand (CCL3 and CCL5) upregulation was observed in the mice during AML (Figure 1C). In addition, significant CCR1 overexpression was found in human TCGA AML samples, associated with a more adverse prognosis (Figure 1D). The role of CCR1 on CM-AML cell expansion in the young mice was validated by either Ccr1 knockout or a selective CCR1 inhibitor (BL5923, Novartis). Consistently, RNAseq data showed that the in vivo inhibitor treatment upregulated the apoptosis gene signature in the LICs (Figure 1E). More importantly, we found that BM CCL3 and CCL5 levels during ageing were similar to those during CM-AML development. In addition, in vivo inhibition of CCR1 significantly impaired CM-AML development in the aged mice (Figure 1F). Summary/Conclusion: Physiological ageing mimics the effect of leukaemic conditioning on the BM microenvironment and directly facilitates AML stem cell propagation. CCR1 signalling is a critical mediator of this effect, suggesting its potential use as a new therapeutic target, especially for elderly AML patients who are ineligible for intensive chemotherapy.Keywords: Acute myeloid leukemia, Aging, Microenvironment